1. Alopecia
Alopecia is a disease in which hair is lost. The loss of hair in alopecia is not limited just to head hair but can happen anywhere on the body. Although not usually life-threatening, since it is accompanied by serious emotional distress due to issues related to appearance, there is a desire for an excellent agent for the treatment and an excellent agent for the prevention of alopecia. Furthermore, since alopecia is often accompanied by fading of hair color, there is a desire for an agent for the prevention and an agent for the treatment of fading of hair color accompanying alopecia. Moreover, since alopecia is often accompanied by deterioration of hair quality such as hair becoming finer or hair becoming shorter, there is a desire for an agent for the prevention and an agent for the treatment of deterioration of hair quality accompanying alopecia.
With regard to types of alopecia, there are alopecia areata, androgenetic alopecia, postmenopausal alopecia, female pattern alopecia, seborrheic alopecia, alopecia pityroides, senile alopecia, cancer chemotherapy drug-induced alopecia, alopecia due to radiation exposure, trichotillomania, postpartum alopecia, etc.
These types of alopecia have the same symptoms of hair loss, but are based on different causes, and therapies therefor are different from each other. In particular, androgenetic alopecia, which is based on the action of male hormone, and alopecia areata, which is suspected to be an immune disease, are very different diseases. Furthermore, it is thought that postpartum alopecia, female pattern alopecia, seborrheic alopecia, alopecia pityroides, senile alopecia, cancer chemotherapy drug-induced alopecia, and alopecia due to radiation exposure have different causes from each other, and there are hardly any effective therapies.
Alopecia areata is alopecia in which coin-sized circular to patchy bald area(s) with a clear outline suddenly occur, without any subjective symptoms or prodromal symptoms, etc. in many cases, and subsequently when spontaneous recovery does not occur they gradually increase in area and become intractable. Alopecia areata is suspected to be an autoimmune disease, but the cause thereof has not yet been discovered, and there is no known definite treatment method.
Alopecia areata is known to be associated with an autoimmune disease such as a thyroid disease represented by Hashimoto's disease, vitiligo, systemic lupus erythematosus, rheumatoid arthritis, or myasthenia gravis or an atopic disease such as bronchial asthma, atopic dermatitis, or allergic rhinitis.
Androgenetic alopecia (AGA) is alopecia in which male hormone acts on male hormone-sensitive hair follicles to form vellus hair, and occurs in about half of males and 10% to 20% of females. It is thought that genetic predisposition is a large factor in androgenetic alopecia; in androgenetic alopecia in males, the head hair on the frontal region and crown becomes fine and short and turns into vellus hair, the hair line on the forehead finally retreats, and head hair on the crown is lost. On the other hand, in androgenetic alopecia in females, in general the hairline does not change but hair of the entire head, in particular the crown and the frontal region, becomes fine. Finasteride improves only about ¼ of patients for androgenetic alopecia in males, and since administration of finasteride to females is contraindicated, finasteride cannot be used for androgenetic alopecia in females.
Postpartum alopecia is alopecia in which hair whose growth phase has been maintained by estrogen enters the resting phase all at once due to childbirth, and hair loss increases. The hair loss of postpartum alopecia usually starts approximately 2 months after childbirth and continues until about 6 months after childbirth; since it usually recovers within 1 year unless there is late childbearing, in most cases a treatment is not particularly required, but there are cases in which hair does not recover spontaneously.
Female pattern alopecia is alopecia that is thought to occur due to a decrease in the amount of the female hormone estrogen relative to the amount of androgen in the bloodstream. It often occurs after the menopause, and in this case it is also called postmenopausal alopecia. Female pattern alopecia might be improved by hormone replacement therapy but is intractable in many cases.
Seborrheic alopecia is alopecia that is caused by excessive sebum secretion on the scalp, pores are blocked thereby causing inflammation around the pores or in the hair root, and the hair falls out. Seborrheic alopecia is improved to some extent by removing sebum by washing the hair, but it easily reoccurs and exhibits intractability.
Alopecia pityroides is alopecia that is caused by dandruff blocking pores to thus cause inflammation. Alopecia pityroides is often caused by excessive hair washing; remission is achieved by reducing the number of times of hair washing or using a shampoo having a weak washing power, but it easily reoccurs and is intractable.
Trichotillomania is alopecia due to a hair-pulling disorder. Trichotillomania is a symptom resulting from pathological anxiety and can be treated by behavioral therapy or psychological therapy.
Senile alopecia is alopecia in which, due to aging regardless of gender, body hair of the entire body, including all of the head hair, gradually becomes thinner. It is thought that this is a natural phenomenon that appears in many people due to aging, and this is not particularly a target for treatment at the present. However, there is a desire for improvement since there is an increased social requirement for improving the quality of life of elderly people accompanying a rise in the average lifespan.
Cancer chemotherapy drug-induced alopecia is alopecia that is a side effect of anticancer treatment with a cancer chemotherapy drug. The shock to the patient caused by loss of hair in all areas including not only the head but also the eyebrows, eyelashes, nasal hair, underarm hair, and pubic hair is profound even if it is explained in advance. Since this also hinders the carrying out of cancer chemotherapy, there is a high need for a treatment for this. Similarly, alopecia accompanying radiation exposure is also alopecia that occurs based on the same mechanism as that for cancer chemotherapy drug-induced alopecia in terms of cancer cells being selectively killed by inhibiting cell division. Therefore, a drug that can treat alopecia accompanying cancer chemotherapy can also treat alopecia accompanying radiation exposure.
In addition, alopecia due to an adverse reaction to a drug such as an antithyroid drug, an anticoagulant, thallium, a psychotropic drug, or a β-blocker, alopecia due to a fungus, alopecia due to an endocrine disorder such as dyspituitarism, hypothyroidism, or hyperthyroidism, alopecia due to a metabolic disorder such as a nutritional disorder, hypoalbuminemia, cachexia, iron-deficiency anemia, zinc deficiency, homocystinuria, or cirrhosis of the liver, toxic alopecia, alopecia due to high temperature, childbirth, major surgery, sudden body weight loss, or serious illness, etc. are known, and they can be tackled by removing the respective causes thereof.
Among these types of alopecia, female pattern alopecia, seborrheic alopecia, and alopecia pityroides can be tackled to some extent by removing the respective causes thereof, but they easily reoccur, and are intractable. Furthermore, although it is thought that the cause of female pattern alopecia is related to hormone balance, hormone replacement therapy is indicated for menopausal disorders, osteoporosis, and hyperlipidemia but is not indicated for female pattern alopecia; since there is a possibility of cancer being caused by hormone replacement therapy, hormone replacement therapy is not carried out for the purpose of treating female pattern alopecia. Furthermore, with regard to androgenetic alopecia, there is no adequate therapy yet, and with regard to alopecia areata, even the cause thereof is little understood.
As described above, among the types of alopecia, the types of alopecia that are difficult to treat are alopecia areata and androgenetic alopecia, and for alopecia areata in particular there are hardly any effective treatment methods. Moreover, there are hardly any therapies for postpartum alopecia, female pattern alopecia, alopecia pityroides, senile alopecia, and cancer chemotherapy drug-induced alopecia.
2. Androgenetic Alopecia and Methods for its Treatment
The frequency of occurrence of androgenetic alopecia increases with age, and in the case of Japanese people, about 10% of people develop it in their twenties, 20% in their thirties, 30% in their forties, and about 40% in their fifties onward (Non-Patent Document 1). In male hormone-sensitive hair follicles such as in the frontal region, the crown, etc., in contrast to hair in other areas, the phenomenon of turning into vellus hair is caused by male hormone to thus cause the head hair to become thin. Although it is a physiological phenomenon, its social effect is large due to the impression of the appearance being greatly affected. Recently, a minoxidil external medicine and a finasteride internal medicine, which are effective for androgenetic alopecia, have been developed and have also been actively used in a dermatological treatment, but it cannot yet be said that sufficient therapeutic effects are obtained.
With regard to medicinal agents that can be used in the treatment of androgenetic alopecia, there are vasodilators such as minoxidil, carpronium chloride, and various extracts, male hormone activity inhibitors such as finasteride, female hormone drugs such as estrogen, estradiol, and progesterone, and antifungal drugs such as ketoconazole, pentadecane, cytopurine (6-benzylaminopurine), t-flavanone, and adenosine.
In ‘Androgenetic alopecia diagnosis and treatment guidelines, 2010 edition’ (Non-Patent Document 2) by the Japanese Dermatological Association, the above-mentioned medicinal agents are evaluated using five grades, that is, recommendation A (strongly recommended for use), recommendation B (recommended for use), recommendation C1 (can be considered for use, but there is insufficient evidence), recommendation C2 (not recommended because there is no evidence), and recommendation D (recommended not to use). In accordance with the above, as a therapy of recommendation A, minoxidil, which is a vasodilator, and finasteride, which is a testosterone 5α-reductase inhibitor, are cited; for minoxidil it is stated that ‘5% minoxidil external solution should be used as the drug of choice in external therapy for a male case, and 1% minoxidil external solution should be used as the drug of choice in treatment for a female case’, and for finasteride internal medicine it is stated that ‘it should be used as the drug of choice in internal therapy for a male case, whereas it should not be used for a female case’. The same guidelines classify carpronium chloride, pentadecane, cytopurine, t-flavanone, adenosine, and ketoconazole as recommendation C1, which is ‘can be considered for use, but there is insufficient evidence’, and classify cepharanthin as recommendation C2 with a written recommendation saying ‘better not used’.
Furthermore, minoxidil has side effects such as drug-induced contact alopecia, hair hyperplasia, decrease of blood pressure, and decrease in heart rate, and there is the problem that when its use is stopped the symptoms recur. With female hormone drugs there is the possibility of thrombosis. Furthermore, finasteride has side effects such as prostate hyperplasia, erectile dysfunction, and ejaculatory disorder, when its use is stopped the symptoms recur, and it is contraindicated for pregnant women.
Furthermore, in accordance with the Drug Interview Form for finasteride (Non-Patent Document 3), the clinical effect of finasteride is confirmed based on evaluation of photographs of the crown. That is, although a hair thickening effect of finasteride on the crown or O-shaped site of androgenetic alopecia has been confirmed, there is no known evidence for a hair thickening effect on hair loss in the frontal region or M-shaped site. Therefore, there is a desire for a new treatment agent that exhibits a clear therapeutic effect toward androgenetic alopecia that continues for a certain period after its use is stopped, exhibits clear effectiveness toward hair loss in areas other than on the crown, and has fewer side effects.
3. Alopecia Areata and Methods for its Treatment
Alopecia areata is a disease that has the highest frequency among acquired alopecias; it occurs in about 0.1% to 0.2% of the population in America, and it seems to be at the same level in Japan. Alopecia areata develops in a person at any age. A quarter of alopecia areata patients develop it at an age of no older than 15 years old, and it is seen relatively often among children. Serious types of alopecia areata such as alopecia totalis or alopecia universalis are relatively often seen among children. There is no gender difference for alopecia areata. About a quarter of alopecia areata patients show characteristic symptoms on the nails, such as a small dent or a horizontal line. With regard to alopecia areata, basically, the wider the hair loss area, the more intractable it is, and classification of severity based on the hair loss area has also been considered (Non-Patent Document 4). Many patients with alopecia areata do not have a physical disorder other than hair loss, but the patients are deeply worried, and the psychological damage and degradation of QOL are great. Because of this, it is considered to be a skin disease that must be treated using any possible method, but there are hardly any effective treatment methods in the current situation.
With regard to the clinical classification of alopecia areata, it is classified according to the number of bald areas, the area, and the configuration as follows.
[1]. Standard alopecia areata
Alopecia areata monolocularis: single bald area
Alopecia areata multilocularis: a plurality of bald areas are observed
[2]. Alopecia totalis: bald patch enlarges to the entire head
[3]. Alopecia universalis: hair loss enlarges to the entire body
[4]. Alopecia ophiasis: band-shaped hair loss occurs at the head hairline
Furthermore, as an index representing severity, USA alopecia areata evaluation guidelines determine severity using the proportion (S) of bald patch area occupying the entire head area and the degree (B) of hair loss other than on the head. Here, they are defined as follows.
S0: No hair loss
S1: Bald patch is less than 25% of the entire head
S2: Bald patch is 25% to 49%
S3: Bald patch is 50% to 74%
S4: Bald patch is 75% to 99%
S5: 100% hair loss
B0: No hair loss in region other than the head
B1: Partial hair loss is seen in region other than the head
B2: Complete hair loss over whole body
The wider the bald patch area in alopecia areata, the more serious the case is, and the more intractable it is.
In recent years, the cause of alopecia areata has been thought to be an autoimmune disease of hair follicle tissue (Non-Patent Document 5). There is also a report that the rate of coexistence of alopecia areata with an atopic disease is relatively high (Non-Patent Document 6). When alopecia is caused by exacerbation of atopic dermatitis it is called atopic alopecia. In particular, atopic alopecia patients having a filaggrin gene abnormality tend to suffer from coexisting serious alopecia areata (Non-Patent Document 7). Histopathologically also, in a group having an atopic predisposition, lymphocyte infiltration into an area around the hair follicle is often seen, and eosinophils and mast cells also infiltrate. Of the infiltrating lymphocytes, CD4-positive T lymphocytes occupy 60% to 80%, CD8-positive T lymphocytes occupy 20% to 40%, and there are a large number of HLA-DR-positive cells and INF-γ-positive cells (Non-Patent Document 8).
However, on the other hand, there is a report that the frequency of an atopic or autoimmune disease in alopecia areata patients is not different from that in healthy people (Non-Patent Document 9). Furthermore, although some relationship between alopecia areata and immune abnormality has been suggested, the specific causal relationship is not at all clear.
As medicinal agents that can be used for the treatment of alopecia areata, there are steroid drugs such as diflorasone, betamethasone, dexamethasone, clobetasol, prednisolone, mometasone, methylprednisolone, Deprodone, difluprednate, fluocinonide, amcinonide, triamcinolone, difluprednate, and hydrocortisone, second-generation antihistamine drugs such as azelastine, Glycyron (registered trademark), which is a complex of glycyrrhizin, methionine, and glycine, carpronium chloride, cepharanthin, minoxidil, cyclosporin A, Cassia Twig plus Dragon's Bone and Oyster Shell Decoction (Keishikaryukotsuboreito), Pinellia and Magnolia Decoction (Hangekobokuto), biotin, Anthralin (Dithranol), tricyclic antidepressants, etc.
Furthermore, as treatments for alopecia areata there are local immunotherapy in which a synthetic reagent called SADBE (squalic acid dibutyl ester) or DPCP (diphenylcyclopropenone) is contacted with a hair loss area to thus form a rash in the hair loss area and modulate immunity, a cooling therapy in which carbon dioxide snow or liquid nitrogen is used, a linearly polarized near-infrared ray irradiation therapy (Super Lizer therapy), a PUVA therapy, which is a photochemical therapy employing in combination Psoralen and long wavelength UV rays (UVA), stellate ganglion block, hypnotherapy, and acupuncture and moxibustion treatments.
With regard to these medicinal agents and therapies, an evaluation was carried out in ‘Japanese Dermatological Association Alopecia Areata Diagnosis and Treatment Guidelines 2010 edition’ (Non-Patent Document 10) using five categories, that is, recommendation A (strongly recommended for use), recommendation B (recommended for use), recommendation C1 (can be considered for use, but there is insufficient evidence), recommendation C2 (not recommended because there is no evidence), and recommendation D (recommended not to use).
In accordance with the above, no therapy is evaluated as recommendation A; as therapies with recommendation B steroid local injection and local immunotherapy are cited, the steroid local injection ‘should be used for monolocularis and multilocularis adult cases where the state of the disease is fixed at S1 or below’, and the local immunotherapy ‘should be carried out as the first choice for multilocularis, totalis, and universalis cases regardless of age where the state of the disease is fixed at S2 or above’. As therapies with recommendation C1, a steroid pulse therapy by intravenous drip infusion is for ‘adult cases of S2 or above rapidly progressing within 6 months after onset’, orally administered steroid or orally administered steroid pulse therapy is for ‘adult cases of S2 or above in which hair loss is rapidly progressing’, and the second-generation antihistamine drug is ‘one of the combined therapies for monolocularis and multilocularis cases having an atopic predisposition’, all being recommended for use with recommendation C1. The same guidelines classify cepharanthin, Glycyron, steroid external preparation, carpronium chloride external preparation, minoxidil external preparation, cooling therapy, linearly polarized near-infrared ray irradiation therapy, and PUVA therapy as recommendation C1 ‘while taking the actual results of diagnosis and treatment into consideration’ even though the ‘benefit is not sufficiently proved at the present stage’.
On the other hand, cyclosporin A and Keishikaryukotsuboreito are classified as recommendation C2 with a written recommendation of ‘cannot be recommended at the current time’. Furthermore, Anthralin, a tricyclic antidepressant, stellate ganglion block, and hypnotherapy are classified as recommendation C2 with a written recommendation of ‘better not used’ or ‘better to withhold’. The acupuncture and moxibustion treatments are classified as recommendation D since they have ‘not reached a standard for medical evaluation’.
With regard to the prognosis for alopecia areata, in a case where the duration of the bald patch is long or a case where there is a history of an atopic disease or an autoimmune endocrine disease, the possibility of a cure is low (Non-Patent Document 11). In accordance with reports from a number of European and American institutions, of all patients, 34% to 50% shift to the totalis type or the universalis type, and in these cases the recovery rate becomes as low as no greater than 10% (Non-Patent Document 12). In adult cases where the hair loss area is less than 50%, 56% thereof recovered, but for alopecia areata with a hair loss area of 50% or greater the recovery rate was only 3.7% (Non-Patent Document 13). Furthermore, the recovery rate is also low for cases in which it developed at the age of 15 or younger or for alopecia ophiasis (Non-Patent Document 12), and there is no recommendable therapy. Therefore, there is a strong desire for development of a new therapy for serious cases of alopecia, in particular S2 or above.
4. Female Pattern Alopecia and Methods for its Treatment
In female pattern alopecia, loss of hormone balance causes a shorter hair growth phase and a longer resting phase. Because of this, the number of hairs emerging from one pore decreases, the hair itself becomes half or less the width of the healthy state, or the hair color becomes pale. As a result, a state in which the scalp is seen through hairs around the center of the crown, that is, a pattern in which it becomes thinner overall, is observed.
Olsen E. et al. 2003 (Non-Patent Document 25) state that the manner of widening of the hair parting from the crown toward the frontal region resembling the manner of spreading of the branches of a Christmas tree is an important initial symptom for female pattern alopecia. Female pattern alopecia usually has an older age of onset than that of androgenetic alopecia, and is often confirmed from the 40s to 50s or after menopause. Since oral administration of finasteride, which suppresses activation of testosterone into dihydrotestosterone, is not effective for menopausal females, it is now generally thought that female thinning hair is not the same as androgenetic alopecia. As herein described, female pattern alopecia is diagnosed, clearly separately from androgenetic alopecia, from gender, age, and a diffuse alopecia state.
With regard to the causes of female pattern alopecia, it is caused by a decrease in estrogen due to the menopause as well as a decrease in female hormone due to severe diet, stress, or suspension of oral contraceptive use.
With regard to treatment for female pattern alopecia, finasteride is contraindicated in practice since it cannot be used for female pattern alopecia of a female who might be pregnant or a female who is breast-feeding. Minoxidil and cepharanthin both have a weak effect on female pattern alopecia. There is no known effect of female hormone replacement therapy on female pattern alopecia. As described above, there are hardly any effective treatment methods for female pattern alopecia.
5. Postpartum Alopecia and Methods for its Treatment
Many females experience the hair becoming thick during pregnancy and hair loss occurring when breast-feeding after childbirth. Since the cause of postpartum alopecia is clear, its diagnosis is easy and it cures spontaneously in many cases, it is not particularly treated. However, it is said that about 40% of postnatal females experience postpartum alopecia, so there are a considerable number of patients. Furthermore, there are variations among individuals for the degree of hair loss of postpartum alopecia and the extent of recovery, and there are rare cases in which hair loss does not stop if postpartum stress continues. In these cases, if a steroid is used for a long period, it often becomes difficult for hair to grow, and this requires attention.
As described above, when postpartum alopecia does not spontaneously recover, a steroid cannot be used for the treatment thereof, and there are no other effective therapies.
6. Seborrheic Alopecia and Methods for its Treatment
In the case of seborrheic alopecia, a large amount of sebum is continuously secreted from the pores, and the pores are blocked to such a degree that it can be seen by the naked eye. Because of this, if sebum is removed, the pores are seen to be red due to inflammation, this inflammation causes hair to be lost, and diagnosis is therefore relatively easy.
With regard to the cause of seborrheic alopecia, it is thought that inflammation is caused by abnormal growth of indigenous bacteria on the scalp due to excessive secretion of sebum; a certain therapeutic effect can be anticipated by appropriately removing sebum in the pores using a less irritating shampoo, but it is difficult to maintain an appropriate level of sebum. It is also said that proliferation of Malassezia globosa, which is a type of fungus, is one factor; there are cases in which external application of an antifungal agent shows a therapeutic effect, but since constitutional secretion of excess sebum is the ultimate factor, it is difficult to improve, and there are hardly any treatments for seborrheic alopecia.
7. Alopecia Pityroides and Methods for its Treatment
Alopecia pityroides is a disease in which a large amount of dandruff is generated abnormally such that dandruff becomes scab-like and blocks the pores to thus cause inflammation, and the diagnosis thereof is relatively easy. With regard to the cause thereof, it is said that indigenous bacteria on the scalp proliferate abnormally due to an abnormal hormone balance, and this gives rise to hair loss.
As a treatment therefor, a steroid treatment exhibits the highest effect among present therapies, but since this method might take a long time to achieve a complete cure or might easily result in a case in which the symptoms become chronic and the treatment becomes rather difficult, it is not a therapy that can be recommended. However, since there is no other therapy in the current situation, in general, the shampoo is changed to one having a weaker washing power, the number of times of hair washing is decreased, or a moisturizer is applied to thus prevent the scalp from becoming dry, with the expectation that the symptoms will be alleviated.
8. Senile Alopecia and Methods for its Treatment
Senile alopecia is alopecia in which, regardless of difference in gender, hair falling out and thinning occur for body hair of the entire body, including the entire head, accompanying aging. As symptoms of senile alopecia, the characteristics of the scalp becoming dry and blood vessels being visible through the skin are often observed. The cause of senile alopecia is due to deterioration in the ability to produce new cells in the body caused by aging, and it is therefore difficult to treat. As a current treatment for senile alopecia, hair papilla are activated by massaging the scalp, etc. to thus improve the possibility of hair growth, and there are hardly any therapies.
9. Cancer Chemotherapy Drug-Induced Alopecia and Methods for its Treatment
Cancer chemotherapy drug-induced alopecia is alopecia that occurs due to a cancer chemotherapy drug inhibiting cell division to thus selectively kill cancer cells, which actively undergo cell division, and at the same time inhibiting hair matrix cells, which also actively undergo cell division in the same manner.
It is known that alopecia is caused by chemotherapy agents such as, for example, cyclophosphamide, ifosfamide, doxorubicin, amrubicin, paclitaxel, docetaxel, irinotecan, epirubicin, etoposide, actinomycin D, bleomycin, vincristine, vinorelbine, carboplatin, methotrexate, cisplatin, melphalan, fluorouracil, gemcitabine, capecitabine, tegafur-gimeracil-oteracil potassium, vinblastine, and ixabepilone, which are generic names.
In general, with regard to cancer chemotherapy drug-induced alopecia, taking the initial administration of a chemotherapy drug as the starting point, hair loss starts after 10 days, hair loss becomes conspicuous after 20 days, and all body hair is lost after 30 to 60 days. With regard to recovery of body hair after completion of cancer chemotherapy, taking completion of administration of the chemotherapy drug as the starting point, hair growth normally starts 3 to 6 months later, and body hair has almost recovered in about 8 to 12 months.
However, since cancer chemotherapy drug-induced alopecia is caused by hair matrix cells within the hair follicle being inhibited by the cancer chemotherapy drug, recovery of body hair after completion of the cancer chemotherapy varies depending on the degree of inhibition of hair matrix cells. Because of this, although there seems to be recovery, even in a mild case the quality of the hair might be degraded and the color or thickness of the hair might change, and in serious cases recovery might be only to the growth of downy hair. Furthermore, even if body hair recovers, since a state in which there is no body hair continues for half a year to one and a half years, the appearance changes greatly during this period and this, coupled with anxiety with respect to the cancer itself, causes considerable distress to the patient.
Objective evaluation of cancer chemotherapy drug-induced alopecia is generally carried out as part of a skin disorder and hair loss evaluation based on Common Terminology Criteria for Adverse Events (CTCAE). Specifically, evaluation by CTCAE of cancer chemotherapy drug-induced alopecia is carried out such that a case without hair loss is evaluated as grade 0, a case with light hair loss is grade 1, and a case with conspicuous hair loss is grade 2.
There is no method for preventing or treating cancer chemotherapy drug-induced alopecia. Therefore, until cancer chemotherapy drug-induced alopecia spontaneously recovers, countermeasures such as a wig being used in place of head hair, eyebrows being drawn by an eyebrow pencil, and artificial eyelashes being used are taken to give a natural appearance.
As described above, alopecia areata, androgenetic alopecia, female pattern alopecia, postpartum alopecia, seborrheic alopecia, alopecia pityroides, senile alopecia, and cancer chemotherapy drug-induced alopecia not only have different causes from each other, but the therapies therefor are also very limited. For example, there are hardly any therapies for female pattern alopecia, postpartum alopecia, alopecia pityroides, senile alopecia, and cancer chemotherapy drug-induced alopecia. Moreover, with regard to androgenetic alopecia, a treatment using minoxidil or finasteride is recommended, but the effects thereof are weak.
Furthermore, for alopecia areata, steroid local injection or local immunotherapy are recommended, and although there are cases in which some effects can be seen, there are many cases in which no effects can be seen at all, and there are cases in which hair grows temporarily but when treatment is stopped the situation deteriorates due to steroid rebound. There is therefore a strong desire for the development of new therapies therefor.
4. Natriuretic Peptides
As natriuretic peptides (NPs), a family of 3 types of natriuretic peptides is known; specifically there are atrial natriuretic peptide (ANP; atrial natriuretic peptide), B-type natriuretic peptide (BNP; B-type natriuretic peptide), and C-type natriuretic peptide (CNP; C-type natriuretic peptide), those formed from 28, 32, and 22 amino acid residues respectively being the ones that are best known.
(1) ANP and BNP
ANP is mainly synthesized in the atrium and BNP is mainly synthesized in the ventricle, and they are then secreted from the heart to the whole body. Substantially 100% of ANP and BNP circulating in the blood is said to be heart-derived. It is reported that ANP and BNP are deeply involved in clinical conditions such as high blood pressure, cardiomegaly, heart failure, myocardial infarction, valvular disease, arrhythmia, and pulmonary hypertension.
Human ANP is a peptide formed from 28 amino acids produced in and secreted from the atrial cells, and forms a cyclic structure due to an intramolecular disulfide bond between cysteine residue 7 and cysteine residue 23. ANP exhibits a diuretic action in the kidney, and it relaxes and expands vascular smooth muscle in blood vessels. On the other hand, human BNP is a peptide formed from 32 amino acids produced in and secreted from the ventricular cells, and forms a cyclic structure due to an intramolecular disulfide bond between cysteine residue 10 and cysteine residue 26. BNP also has a diuretic action and a vasodilating action. BNP is a peptide that was isolated from pig brain in 1988 and identified, and is also called brain natriuretic peptide.
Both ANP and BNP bind to an NPR-A receptor having a guanylate cyclase domain (also called GC-A), promote the production of cGMP, and exhibit the above-mentioned action. In reality, secretion of ANP is promoted accompanying an increase in atrial inflation pressure in congestive heart failure, etc., and it functions to alleviate the symptoms of congestive heart failure, etc. by virtue of the above-mentioned action. Secretion of BNP is also promoted in myocardial infarction, etc., and it functions to alleviate various symptoms accompanying myocardial infarction, etc. by virtue of the above-mentioned action (Non-Patent Document 14). Most BNP in the blood is derived from the ventricle, but some is also secreted from the atrium. Expression of both ANP and BNP is increased to 100 times the normal level in a heart failure state, but it is also reported that the increase of BNP is larger and faster than that of ANP. ANP (hANP) is commercially available in Japan as an acute heart failure treatment drug, and in the USA BNP is commercially available as a congestive heart failure treatment drug.
(2) CNP
Because CNP was first discovered in the brain, it was thought that it functioned as a cranial nerve peptide, but it was later found that it also exists in the periphery. In particular, since in the blood vessel wall there are many CNP-specific receptors in smooth muscle cells, monocyte/macrophage cells and endothelial cells produce CNP, etc., it is thought that CNP is involved in the suppression of growth of smooth muscle cells as a local factor in the blood vessel wall. Because of this, the possibility of administration of CNP being able to prevent intravascular restenosis, which occurs with a certain frequency among patients with an ischemic heart disease after receiving percutaneous transluminal coronary angioplasty (PTCA) and is a clinical problem, is currently being examined in terms of clinical application.
Furthermore, an animal experiment has recently been reported in which intravenous administration of CNP clearly improves enlargement of the heart and fibrosis after myocardial infarction and improves the cardiac function. Fibrosis of the heart is known to cause diastolic heart failure or arrhythmia, and since CNP has the action of strongly suppressing the growth of fibroblasts, research has been carried out into its use as a drug for the treatment of fibrosis of the heart. Since CNP is a hormone present in the body, there are no concerns about side effects, and its application as a clinical treatment drug for arteriosclerotic disease or cardiac disease is anticipated. As CNP, CNP-22 having 22 amino acids, CNP-53 having 53 amino acids in which amino acid residues are added to the N terminal of the above, etc. are known.
(3) Natriuretic Peptide Receptors
As receptors for NPs, three types are known, that is, an NPR-A receptor having a guanylate cyclase domain (also called GC-A), an NPR-B receptor having a guanylate cyclase domain (also called GC-B), and an NPR-C receptor having no guanylate cyclase domain, and it is known that ANP binds to the NPR-A receptor and the NPR-C receptor, BNP binds to the NPR-A receptor and the NPR-C receptor, and CNP binds to the NPR-B receptor and the NPR-C receptor.
It is said that activation of the NPR-A receptor brings about vasodilatory action, diuretic action, and cytostatic action. On the other hand, NPR-B receptors are present in large numbers in vascular smooth muscle cells, and are thought to bring about growth-inhibition action for vascular smooth muscle cells. The NPR-C receptor is also called a clearance receptor and is though to remove NPs in blood and regulate the concentration of NPs in tissue.
(4) Relationship Between Natriuretic Peptides and the Immune System
With regard to natriuretic peptides, historically ANP was first discovered as a peptide secreted by the atrium, and its vasodilatory action and diuretic action have received attention. Following this, BNP and CNP were found as peptides analogous to ANP. Due to such historical reasons, with regard to the relationship between natriuretic peptides and immunity, those related to the cardiovascular system have attracted attention.
Furthermore, following this, because of poor growth of the cartilage it has been found that a CNP knockout mouse exhibits a microsomia-like phenotype (Non-Patent Document 15), and since CNP is anticipated to promote regeneration of articular cartilage, the relationship between arthritis and natriuretic peptides is also attracting attention. However, there is no mention in this publication of a relationship between CNP and alopecia.
It has been suggested that ANP has a role in arthritis or septicemia since it suppresses secretion by macrophages of tumor necrosis factor α (INF-α) and interleukin 1β (IL1β), which are inflammatory cytokines (Non-Patent Document 16). However, there is no mention in this publication of a relationship between ANP and alopecia.
Furthermore, since it has been reported that the concentration of BNP in blood increases in parallel to heart transplant rejection, it has been suggested that it is involved in immune modulation in the cardiovascular system (Non-Patent Document 17). However, there is no mention in this publication of a relationship between BNP and alopecia.
Kuroski de Bold et al. have examined the immunomodulating action of natriuretic peptides while noting an increase in the concentration of BNP in blood at the time of heart transplant rejection and have found that ANP and BNP both suppress lymphocyte proliferation (Non-Patent Document 18). However, there is no mention in this publication of a relationship between NP and alopecia.
On the other hand, Chiurchiu et al. have examined the immunomodulating action of BNP while noting the relationship with cardiac disease and septicemia and have reported that since BNP promotes the release by macrophages of arachidonic acid, prostaglandin E2 (PGE2), and leucotriene B4 (LTB4), which are inflammatory cytokines, and interleukin 10 (IL10), which is an anti-inflammatory cytokine, it has some type of action in modulating inflammation, but they could not conclude whether or not it functions to suppress or promote inflammation overall (Non-Patent Document 19). There is no mention in this publication either of a relationship between BNP and alopecia.
It has been reported that CNP is secreted from macrophages (Non-Patent Document 20). Furthermore, Scotland et al. have reported that CNP suppressed platelet aggregation and leucocyte migration during the course of examining the role of CNP in myocardial damage after cardiac ischemia and reperfusion (Non-Patent Document 21). However, there is no mention in these publications of a relationship between CNP and alopecia.
Similarly, Obata et al. have examined the action of CNP in myocarditis and have reported that when pig myosin was injected into a rat myocarditis model and CNP was administered continuously for 1 week following this, necrosis and inflammation of the heart tissue were suppressed, angiogenesis was promoted, and deterioration of cardiac function was suppressed (Non-Patent Document 22). However, there is no mention in this publication of a relationship between CNP and alopecia.
Furthermore, since CNP knockout mice show a microsomia-like phenotype, CNP is attracting attention in terms of the relationship with the growth of cartilage. Agoston et al. have found that, in primary culture of cartilage cells separated from mouse embryo neckbone, dexamethasone increases expression of the CNP gene (Non-Patent Document 23). However, there is no mention in this publication of a relationship between CNP and alopecia.
As hereinbefore described, in recent years, the relationship between immunity and natriuretic peptides has been attracting attention, but it is only the relationship between cardiovascular inflammation and natriuretic peptides or between arthritis and natriuretic peptides that is attracting attention, and there is no report of a relationship between alopecia and natriuretic peptides.
(5) Reports on Applications Related to Natriuretic Peptides
There are a large number of reports on the application of ANP, BNP, and CNP as described below in addition to the above. However, none of these publications refer to a relationship between natriuretic peptides and specific types of alopecia such as alopecia areata, androgenetic alopecia, alopecia pityroides, postpartum alopecia, female pattern alopecia, seborrheic alopecia, trichotillomania, and senile alopecia. Furthermore, none of these publications demonstrate that CNP or BNP is useful for the treatment of alopecia.
Shoji Tanaka et al. have proposed C-type natriuretic peptides exhibiting growth-inhibitory action for vascular smooth muscle cells and a vascular smooth muscle growth inhibitor containing these peptides as an active ingredient (Patent Document 1).
However, this means the use of CNP as an agent for the inhibition of smooth muscle cells and does not suggest the application of CNP or BNP to an agent for the treatment of alopecia.
Katsuhiko Nakata et al. have proposed an eye dropper for the promotion of lacrimal secretion or the treatment of keratoconjunctival disorder that contains a natriuretic peptide as an active ingredient, and ANP, BNP, and CNP are cited as natriuretic peptides that can be used (Patent Document 2).
However, this concerns utilization of the action of ANP, BNP, and CNP in promotion of lacrimal secretion as an eye dropper for the treatment of keratoconjunctival disorder, and does not suggest the application of CNP or BNP to an agent for the treatment of alopecia.
Kazuwa Nakao et al. have proposed a composition for increasing height that is administered to an individual having no FGFR3 abnormality and contains a guanyl cyclase B (GC-B) activator such as CNP as an active ingredient (Patent Document 3).
However, the intention was to utilize CNP as a composition for increasing height based on the knowledge that the length between the nose and the anus is larger for a transgenic mouse overexpressing CNP than for a normal littermate, and does not suggest any application of CNP or BNP to an agent for the treatment of alopecia.
Similarly, Kazuwa Nakao et al. have proposed an agent for the treatment or prevention of arthritis, the agent containing a guanyl cyclase B (GC-B) activator such as CNP as an active ingredient (Patent Document 4).
However, this is only a finding that in a transgenic mouse overexpressing CNP, the thickness of the articular cartilage is large compared with a normal littermate, and when CNP is continuously administered to an arthritis model animal, the arthritis is suppressed, the intention being to utilize CNP as an agent for the treatment or prevention of arthritis, and does not suggest the application of CNP or BNP to an agent for the treatment of alopecia.
Similarly, Kazuwa Nakao et al. have proposed an agent for the prevention or treatment of fatty liver that contains a GC-A receptor agonist as an active ingredient since in a BNP transgenic mouse overexpressing BNP there is resistance to fat increasing with a high-fat diet load and the glucose tolerance and insulin sensitivity are improved, and a hetero knockout mouse with respect to a gene for GC-A receptor, which is a receptor for ANP and BNP, easily becomes fat with a high-fat diet load, and the glucose tolerance and insulin sensitivity are impaired (Patent Document 6).
However, this does not suggest the application of a natriuretic peptide to an agent for the treatment of alopecia and does not mention CNP at all.
Isao Sakaida et al. have proposed an agent for suppressing hepatic fibrosis that contains a natriuretic peptide as an active ingredient based on the finding that when ANP or CNP was continuously administered to rats together with N-diethylnitrosoamine, hepatic fibrosis due to N-diethylnitrosoamine was suppressed (Patent Document 7).
However, the intention was to use a natriuretic peptide for prevention of cirrhosis of the liver or liver cancer, and there was no suggestion of the application of a natriuretic peptide to an agent for the treatment of alopecia.
Yasuhiko Ito et al. have proposed an agent for suppressing peritoneal fibrosis that contains a natriuretic peptide as an active ingredient based on the finding that when ANP was continuously administered to a rat abrasion-induced peritoneal fibrosis model, the peritoneal fibrosis was suppressed (Patent Document 8).
However, the intention was to use a natriuretic peptide for suppression of peritoneal fibrosis at the time of peritoneal dialysis and there was no suggestion of the application of a natriuretic peptide to an agent for the treatment of alopecia.
Chen et al. have proposed a peritoneal dialysis solution containing ANP based on the finding that when a peritoneal dialysis solution containing ANP was injected into a rat, net ultrafiltration and sodium clearance increased (Patent Document 9).
However, the intention was to add ANP to a peritoneal dialysis solution and apply it to the treatment of a patient with kidney damage, and there was no suggestion of the application of a natriuretic peptide to an agent for the treatment of alopecia.
Toshiyuki Hori et al. have proposed an agent for the prevention or treatment of a Th1 immune disease that contains a GC-A receptor agonist as an active ingredient based on the finding that when LPS is added to a medium the proliferation of naive T cells induced by dendritic cells was suppressed by the simultaneous addition of ANP (Patent Document 10).
However, the intention was to apply ANP to the prevention or treatment of a Th1 immune disease such as Crohn's disease, and there was no suggestion of the application of a natriuretic peptide to an agent for the treatment of alopecia.
Hisako Koide et al. have proposed a preparation for repair and regeneration of tissue and organ that contains as an active component ANP, BNP, CNP, Urodilatin (P-Uro), a precursor thereof, a derivative thereof, or a combination thereof, and which may contain a pharmaceutically acceptable diluent, excipient, filler, or adjuvant, and have cited, as one example of the repair and regeneration of tissue and organ, hair restoration, hair growth, and hair thickening (Patent Document 5). Furthermore, in Example 3 of the same publication, it was reported that when ANP was applied twice a day after hair washing to the scalp of ‘54 year old and 89 year old males with thin head hair’, ‘downy hair-like hair growth was observed on the frontal region with 1 week of ANP administration, and sites started to appear where black hair papilla appeared after hair had fallen out’, ‘after 2-3 weeks, resilience and rigidity increased for the entire head hair’, and ‘after 1 month the scalp, which could been seen before use, was obviously difficult to see’.
However, Patent Document 5 describes only hair growth due to ANP and does not demonstrate any of hair restoration, hair growth, and hair thickening by CNP or BNP. Furthermore, with regard to alopecia, there are various types of alopecia in terms of the cause, and their therapies are very different from each other, but the mere description of ‘54 year old and 89 year old males with thin head hair’ cannot clarify for which type of alopecia an effect was exhibited; since the characteristic that ‘the foremost line of retreating head hair moved forward’ is a characteristic that can be seen in various types of alopecia, it is not clear what kind of cause or disease the ‘thin hair’ is derived from. Furthermore, said publication only considers a ‘drug for hair growth, hair restoration, and hair thickening’ as a very broad concept; it is unclear whether it is a treatment agent or a preventive agent, and it does not suggest a treatment or preventive agent for a specific alopecia and does not suggest a treatment or preventive agent for dandruff, white hair, and seborrheic scalp. It is therefore clear that this publication does not suggest an agent for the treatment or prevention of alopecia areata, androgenetic alopecia, postpartum alopecia, female pattern alopecia, seborrheic alopecia, alopecia pityroides, senile alopecia, cancer chemotherapy drug-induced alopecia, alopecia due to radiation exposure, dandruff, white hair, and seborrheic scalp.
Shoji Tanaka et al. have announced as described below that CNP has a completely different structure and effect from those of ANP and BNP (Patent Document 1).
‘It is currently thought that ANP and BNP both function as a hormone secreted from the heart into the blood, also function as a neurotransmitter, and play an important role in maintaining homeostasis in the fluid volume and blood pressure of a living body . . . there are many unclear points regarding the physiological role of CNP as an NP. That is, the amino acid primary sequence of CNP is similar to those of ANP and BNP; furthermore, it exhibits natriuretic action and hypotensive action by in vivo administration, and it is therefore classed as belonging to the NP family. However, since the natriuretic action and hypotensive action of CNP are much weaker than those of ANP and BNP ( 1/50 to 1/100) . . . CNP occupies a specific position within the NP family, and it is assumed that with regard to its physiological role, it might play a role other than maintenance of homeostasis in the fluid volume and blood pressure . . . when the structure of CNP is compared with those of ANP and BNP, it can be seen that CNP is different from ANP or BNP in terms of the points described below . . . . That is, it can be seen that the amino acid primary sequence of CNP is completely different from that of ANP or BNP for the exocyclic N-terminal domain, and within 17 amino acid residues in the endocyclic domain it is different from ANP by 5 residues and from BNP by 4 residues. Furthermore, the structure of the exocyclic C-terminal domain of CNP is very different from those of ANP and BNP, CNP does not have a tail structure, which is present in ANP and BNP (in the case of ANP and BNP, there are 5 amino acid residues added to the C-terminal of the cyclic structure for ANP and 6 amino acid residues for BNP, and these structures are called tail structures for convenience). It is clear that the above-mentioned difference in structure between CNP and ANP or BNP is involved in exhibition of the above-mentioned characteristic pharmacological action of CNP.’
In reality, as shown in FIG. 1 also, ANP, BNP, and CNP have very different structures and are thought to carry out different roles from each other.